Drug addiction is a chronic and debilitating disorder that has an immense social and financial impact on individuals and society. Drugs of abuse are believed to elicit changes in neural circuits that ultimately manifest themselves in a variety of self-destructive behaviors. Emerging evidence indicates that synaptic plasticity is important for functional changes of neurons in addiction. However, the molecular mechanisms involved are only partly understood. Glial cells could be a key element in regulating brain plasticity associated with addiction as discoveries over the last decade have revealed that glia contain proteins modulated by drugs of abuse and can regulate synaptic function. Indeed, glial cells help define neurotransmitter levels at the synapse, buffer the extracellular milieu, and release factors that modulate synaptic development and strength. Interestingly, recent advances in the field have found that glia also control homeostatic adaptations of neural connections in response to changes in activity through secretion of the cytokine TNF?. TNF? is a key player in immune and inflammatory responses, but is also released by glia following activity deprivation of neurons. TNF? increases synaptic efficacy by controlling the trafficking of AMPA and GABA-A receptors into and out of synapses, respectively. Thus, communication between astrocytes and neurons through TNF? may be important for reprogramming synaptic strength, for instance during exposure to drugs of abuse. The overall goal of this proposal is to investigate the crosstalk between TNF?-mediated changes in synaptic plasticity with alterations in neuronal function induced by drugs of abuse. To do this, we will (1) investigate how TNF? modulates the behavioral response to drugs of abuse, (2) determine how drugs of abuse interact with glial-derived TNF? in controlling synaptic homeostasis and morphology, and (3) identify mechanisms that regulate TNF? production in response to drugs of abuse. The proposed studies will increase our understanding of glial mechanisms that regulate synaptic plasticity following substance abuse. Furthermore, these studies may enable the development of pharmaceutical approaches that modulate cellular and molecular changes associated with addiction. PUBLIC HEALTH RELEVANCE: Drug addiction is a chronic and debilitating disorder that places an immense social and financial burden on individuals and society. Drugs of abuse are believed to elicit adaptive changes in neural circuits that ultimately manifest themselves in a variety of self-destructive behaviors. The proposed studies will increase our understanding of glial mechanisms that contribute to synaptic changes in response to drugs of abuse and may be useful for the development of treatments for addiction.